An essential step towards understanding the function of a brain structure is to understand the intricacies of its neuronal interconnections. Extensive evidence suggests that neurons in the cerebral cortex are interconnected into functional columns. Moreover, columns with similar physiological properties are arranged close to each other and lead to the formation of cortical maps. At the level of neuronal populations, cortical maps varied smoothly across the surface of the cortex. However, recent studies demonstrate that neurons next to each in the cerebral cortex can have drastically different physiological properties, arguing that the microcircuit in functional columns is highly specific at the level of individual neurons. Given the daunting complexity in the number and type of neurons in the cerebral cortex, the formation of this fine-scale microcircuit is a seemingly bewildering task. This raises an intriguing possibility whether the formation of precise microcircuits in the cerebral cortex depends on the highly regulated processes underlying the early cortical development, e.g. neurogenesis and neuronal migration. It has been previously suggested that the formation of functional columns is related to ontogenetic radial units, the construction units of the cerebral cortex that consist of individual radial glial progenitor cells and associated daughter cells - migrating cortical neurons. To test this hypothesis, it is essential to identify ontogenetic radial units in the development cortex and investigate their morphological and functional development. In this project, we will develop new experimental and computational tools to label ontogenetic units of excitatory and inhibitory neurons in the developing cortex, analyze their morphological development, and map their synaptic connectivity. Specifically, we will engineer retroviruses that express fluorescence proteins and use them to infect dividing radial glial progenitor cells in the developing cortex in vivo in a cell/tissue specific manner. The morphogenesis of individual ontogenetic radial units expressing fluorescent proteins will be analyzed using state-of-the-art imaging techniques and powerful imaging analysis tools. Furthermore, we will combine whole-cell electrophysiological recordings with the latest development of photostimulation techniques to investigate the microcircuit development among neurons in ontogenetic units at single-cell resolution. The proposed research promises a wealth of new insights into the developmental and functional organization of the cerebral cortex. It will also facilitate the understanding and treatment of various neurological and psychiatric disorders caused by the cerebral cortex malformation and malfunction. PUBLIC HEALTH RELEVANCE This project will develop new experimental and computational tools for labeling neurons in the cerebral cortex that share the same origin and for investigating their morphological and functional development. It will advance and expand the understanding and treatment of a variety of neurological and psychiatric disorders caused through defects in cerebral cortex development and function, such as mental retardation, epilepsy, autism, and maladaptive decision-making behavior associated with drug abuse.